|Year : 2020 | Volume
| Issue : 3 | Page : 141-146
Examination of ototoxicity induced by imatinib, being a tyrosine kinase inhibitor: An experimental study
Emine Elif Altuntas1, Kasim Durmus1, Adem Bora1, Nergiz Hacer Turgut2, Hatice Terzi3, Ahmet Kutluhan4
1 Department of Otolaryngology, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
2 Department of Pharmacology, Faculty of Pharmacy, Izmir Katip Celebi University, Izmir, Turkey
3 Department of İnternal Medicine, Faculty of Medicine, Sivas Cumhuriyet University, Sivas, Turkey
4 Department of Otolaryngology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
|Date of Submission||16-Jun-2020|
|Date of Acceptance||21-Jul-2020|
|Date of Web Publication||22-Dec-2020|
Prof. Emine Elif Altuntas
Department of Otolaryngology, Faculty of Medicine, Sivas Cumhuriyet University, 58140 Sivas, Ankara
Source of Support: None, Conflict of Interest: None
Objectives: Two rats were excluded from the study. Because otitis media developing one rat in Group C (7th dayof the experiment) and bleeding-related death one rat in Group I-50 (14th day of the experiment). While the side effects of imatinib are investigated in the literature, it is remarkable that the case reports suggesting an ototoxic side effect also take place among the publications. The aim of this study was to investigate whether or not imatinib has any ototoxic effect on rats via auditory brainstem response (ABR) responses. Materials and Methods: Rats were divided into three groups as Group C (0.25 mL/kg/day), Group I-30 (30 mg/kg/day), and Group I-50 (50 mg/kg/day). In the ABR record, hearing threshold, latency, amplitude, and interpeak latency values on test days were recorded and assessed. Results: In the assessment made in terms of mean V Wave latency within the group, a difference was determined at all stimulus intensities at 8 kHz in Group I-50 (P < 0.05). In the within-group assessment performed in terms of mean Wave III latency, there were differences in Groups I-30 and I-50 (P < 0.05). In the within-group assessment performed in terms of I–III interpeak latency mean values, there was a difference at 4 kHz and 70 dB in Group I-30 (P < 0.05). In the within-group assessment in terms of mean III–V interpeak latency values, the difference between the groups was significant on the 7th day at 6 kHz and 50 dB (P = 0.044) and on the 14th day at 8 kHz and 70 dB (P = 0.036). In the within-group assessment in terms of Wave I amplitude mean values, the change in the amplitude values at 4 kHz (P = 0.003) and 6 kHz (P = 0.018) in Group I-50 was significant. Conclusion: It was observed that imatinib application caused elongation in latency and interpeak latency values and changes in amplitude values. These differences were not enough to state that imatinib is having an ototoxic side effect.
Keywords: Auditory brainstem response, imatinib, hearing loss, ototoxicity, rat
|How to cite this article:|
Altuntas EE, Durmus K, Bora A, Turgut NH, Terzi H, Kutluhan A. Examination of ototoxicity induced by imatinib, being a tyrosine kinase inhibitor: An experimental study. Indian J Otol 2020;26:141-6
|How to cite this URL:|
Altuntas EE, Durmus K, Bora A, Turgut NH, Terzi H, Kutluhan A. Examination of ototoxicity induced by imatinib, being a tyrosine kinase inhibitor: An experimental study. Indian J Otol [serial online] 2020 [cited 2021 Jan 17];26:141-6. Available from: https://www.indianjotol.org/text.asp?2020/26/3/141/304281
| Introduction|| |
The sensitivity of the inner ear against various chemicals has been known for centuries. Ototoxicity is a general concept used to describe hearing loss and balance disorder due to damage occurring on the cochlear and the vestibular organ upon the confrontation with various therapeutic agents and chemicals. It is known that many commonly used agents (e.g., antibiotics, diuretics, anti-inflammatories, and antineoplastics) cause ototoxicity. Although the mechanisms of drugs causing ototoxicity are not exactly known, it is known that they may show ototoxic effects by causing neurotoxicity, increased oxidative stress, and vascular occlusion.,,
In parallel with the rapid developments in the pharmaceutical industry, many new drugs are introduced to the market every day. The effects of all these drugs on the cochlea and vestibular nerve in the early or late period are not known certainly. Whether or not these newly developed drugs have ototoxic effects often reveals accidentally during their clinical use, and then, these aspects are presented by experimental or clinical trials.
Small molecule tyrosine kinase inhibitors are also highly novel antineoplastic agents that are developed to deteriorate the essential cancer cell functions such as proliferation and differentiation by blocking the signal pathways in the tumor cells. Imatinib mesylate is the first tyrosine kinase inhibitor that is shown to be effective in cancer treatment., The success of imatinib mesylate in the treatment of chronic myeloid leukemia (CML) is a first in terms of target-specific treatments. Tyrosine kinase inhibitors have become the first treatment option in adult CML patients. Although it is required to use imatinib for lifelong in CML patients, it is an important advantage that the drug has few side effects such as peripheral and periorbital edema, muscle cramps, gastrointestinal intolerance, skin rash, hepatotoxicity, and rarely seen congestive heart failure.,, While the side effects of imatinib are investigated in the literature, it is remarkable that the case reports suggesting an ototoxic side effect also take place among the publications. At this point, when “Imatinib (Gleevec) hearing loss” was written as a key word in the PubMed and Google Scholar databases, a total of six studies were found. These studies were shared with the literature between 2007 and 2015 and some of them have pointed out that there may be a correlation between hearing loss and imatinib, and further clinical and experimental studies should be performed in terms of an ototoxic effect.,,,,
No clinical or experimental study investigating the correlation between imatinib and hearing loss was found in the literature review. Current publications have caused the formation of “Is Imatinib an ototoxic antineoplastic drug?” hypothesis and the formation of an idea for seeking an answer for this question. From this point of view, the aim of the present study was to investigate experimentally whether or not different doses of imatinib administration have an ototoxic effect in rats via the auditory brainstem-evoked potential responses (ABRs).
| Materials and Methods|| |
The study was conducted within the scope of Audiology and Speech Disorders doctorate program of Ankara Yıldırım Beyazıt University. Experiments were performed at Sivas Cumhuriyet University Faculty of Medicine Experimental Research and Animal Laboratory by taking the approval of Sivas Cumhuriyet University Animal Experiments Local Ethics Committee (dated January 5, 2017, and no. 65202830-050.04.04-10) according to the Guide for the Care and Use of Laboratory Animals of National Institute of Health (NIH) (NIH Publications No. 80-23 Revised 1996).
The randomized experimental procedure was used in the study, and external ear canals and eardrums of 30 rats, which were anesthetized with 3 mg/kg xylazine S. C. and 90 mg/kg ketamine HCL S. C., were examined with an operating microscope (Zeiss, Germany) for selection of the rats. Rats with external and middle ear pathologies were excluded from the study. Twenty-four male Wistar albino rats being aged between 16 and 18 weeks and weighing 230 ± 10 g in average were used in the study. The rats were kept under standard laboratory conditions (12-h light/dark cycle, 24 ± 2°C, 35%–60% humidity) in steel cages and fed with fresh bait without any nutrient limitation.
Two different dosages of imatinib used in the studies investigating the cardiotoxic effect of imatinib on rats were taken as a basis and used in the experimental procedure., Wistar albino rats (n = 24) were randomly divided in three groups as Group C (control; 0.25 mL/kg/day; n = 8) distilled water, Group I-30 (30 mg/kg/day; n = 8) imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) dissolved in distilled water, and Group I-50 (50 mg/kg/day; n = 8) dissolved in distilled water (when α = 0.05, β = 0.20, [1−β] = 0.80 values were considered, it was decided to include 8 rats in each group and the test strength was found as P = 0.80942). Imatinib (Groups I-30 and I-50) dissolved in distilled water and distilled water (Group C) was administered to all the rats in the experimental groups at the abovementioned doses at the same time every day and in a single dose for 21 days by gastric gavage.
The rats died for any reason during the experimental phase were excluded from the experimental protocol. Two rats were excluded from the study because of otitis media developing and bleeding-related death. Furthermore, each rat was weighed one by one before the hearing evaluation, and the changes in the drug-related weight loss and general health status were recorded. No significant weight loss or general condition disorder was observed in any of the 22 rats in all three groups during the experiment.
Drug and chemicals
Imatinib mesylate was obtained from Novartis Pharmaceuticals (Gleevec; Basel, Switzerland) and was provided to have its purity at analytical grade by dissolving in distilled water. The daily doses for the rats in each group were prepared individually by an academic member (NHT) working at the Department of Pharmacology of Pharmacy Occupational Sciences Division of Faculty of Pharmacy, XXX YYYY University.
After the rats participating in the study were anesthetized using 3 mg/kg xylazine S. C. and 90 mg/kg ketamine HCL S. C., ABR thresholds were recorded in a quiet room using a GN Otometrics ICS Chartr EP 200 (Denmark) device on the 0th day [the beginning of the study] (before administering orally any drug or distilled water via gastric gavage) and 7th, 14th, and 21st days (after administering drug or distilled water). ABR measurements of all the rats were done from the right ear. Records of ABRs were taken using subcutaneous Natus Ultra Subdermal Needle Electrode (Stainless Steel Needle DIN 42802 Connector, Natus Neurology Incorporated 3150 Pleasant, View Road Middleton, WI 53562, USA, Indonesia) Electrode placement was carried out as being on an active electrode vertex, on the grounding electrode contralateral mastoid, and reference electrode ipsilateral mastoid. Stimuli were given by insert earphones. ABR evaluation was performed at 30, 50, and 70 dB stimulus intensity by tone-burst stimulus at 4, 6, and 8 kHz. The stimulus was started to be given at 70 dB SPL level, and it was decreased by 20 dB until the intensity level is approached to the threshold. When the threshold was approached, 10 dB intensity steps were preferred, and the threshold was determined. At least two traces were generated for each measurement, behavioral reproducibility was tested, and checking was performed for threshold determination. In case that no behavior could be obtained at 70 dB Sound Pressure Level (SPL) level, a 90 dB SPL stimulus level was used.
Stimuli were submitted at alternated polarity; filter was adjusted as 30–1500 Hz, repetition rate as 37/s, and time window as 25 msec, and 1024 samples were taken for taking the average of the signal. The test was started by verifying that impedance had lower values than 1.0 kΩ. ABR threshold was defined as the minimum intensity level with visible V Wave of ABR. The auditory threshold of 10 dB level was accepted as the inclusion criteria.
In addition to the threshold values, latency, amplitude, and interpeak latency values were recorded on the 0th, 7th, 14th, and 21st days in the ABR recordings in all the rats. Latency value was measured in milliseconds. In the study, absolute latencies were evaluated at 70 and 50 dB SPL for Wave III and at 70, 50, and 30 dB SPL for Wave V. Amplitude values were measured at 70 dB stimulus intensity level of the Waves I, III, and V. Interpeak latency is generally accepted as the transmission time of the central auditory duct; interpeak latencies of the Waves I–III, III–V, and I–V reflect the crossing times in the caudal, rostral, and whole brainstem, respectively. The elongation in the interpeak latencies is an indicator of a pathology in central auditory processing. Thus, in the study, I–III, I–V, III–V interpeak latencies were measured at 70 dB SPL stimulus intensity.
The Statistical Package of the Social Science (SPSS Inc., Chicago, IL, USA) for Windows 23.0 packaged software was used for the evaluation of the data obtained. In the assessment of data obtained from the present study, it was determined that despite the results according to the Kolmogorov–Smirnov Z test, the results did not fulfill the parametric test hypothesis (P < 0.05); Mann–Whitney U test was used for the independent samples in two-category comparisons, Wilcoxon signed-rank test for dependent samples, Kruskal–Wallis H test for independent samples for the comparison with more than two categories, and Friedman F test for dependent samples. The tests were interpreted at confidence level of 95%.
| Results|| |
In the 0th, 7th, 14th, and 21st-day ABR assessment performed in all the rats included in the study, the Wave V was observed at 4, 6, and 8 kHz frequencies and at 10 dB stimulus intensity.
No statistically significant difference was determined at three frequencies and stimulus intensity levels in the average latency values in Wave V in Groups C and I-30 (P > 0.05). However, a statistically significant difference was detected at all the stimulus intensity levels at 8 kHz in Group I-50 in all of 4 days of evaluation (P < 0.05) [Table 1]. There was no statistically significant difference between the groups in terms of average latency values of the Wave V (P > 0.05).
|Table 1: Wave V latency mean values of the rats in Group I-50 on the 0th, 7th, 14th, and 21st days in auditory brainstem response assessment|
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While no statistically significant difference was found in all the three frequencies and stimulus intensity levels in Group C in intragroup assessment in terms of average latency values of the Wave III (P > 0.05), there were statistically significant differences in Groups I-30 (4 kHz – 50, 70 dB and 6 kHz – 50 dB) and I-50 (4 kHz – 50, 70 dB and 8 kHz – 50, 70 dB) (P < 0.05) [Table 2]. There was no statistically significant difference between the groups in terms of average latency values of the Wave III (P > 0.05).
|Table 2: Wave III latency mean values of the rats in Groups I-30 and I-50 on the 0th, 7th, 14th, and 21st days in auditory brainstem response assessment|
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No statistically significant difference was determined in Groups C and I-50 in the intragroup assessment performed in terms of interpeak latency average values of Waves I–III (P > 0.05). There was a statistically significant difference at 4 kHz and 70 dB in Group I-30 (P < 0.05) [Table 3]. Similarly, there was no statistically significant difference between interpeak latency average values of Waves I–III in intergroup assessment (P > 0.05).
|Table 3: I-III interpeak latency mean values of the rats in Groups I-30 on the 0th, 7th, 14th, and 21st days in auditory brainstem response assessment|
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No statistically significant difference was determined in the intragroup assessment performed in terms of interpeak latency average values of Waves I–V (P > 0.05). Similarly, no statistically significant difference was detected among the groups in terms of the interpeak latency average values of the Waves I–V (P > 0.05).
No statistically significant difference was determined in all three groups in the intragroup assessment performed in terms of interpeak latency average values of the Waves III–V (P > 0.05). In the intergroup assessment, the difference among the groups was significant on the 7th day at 6 kHz and 50 dB (P = 0.044) and on the 14th day at 8 kHz and 70 dB (P = 0.036).
Amplitude values were measured at 70 dB stimulus intensity of the Waves I, III, and V.
While no statistically significant change was observed in the amplitude mean values of the Wave I in Groups C and I-30 in the intragroup assessment (P > 0.05), the change in the amplitude values in Group I-50 at 4 kHz (P = 0.003) and 6 kHz was statistically significant (P = 0.018) [Table 4]. There was no statistically significant difference among the groups in terms of amplitude mean values of the Wave I.
|Table 4: Amplitude mean values of the Wave I of the rats in Groups I-50 on the 0th, 7th, 14th, and 21st days in auditory brainstem response assessment|
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No statistically significant difference was observed at all three frequencies in the amplitude mean values of the Wave III on the assessment days in all three groups in the intragroup assessment (P > 0.05). Similarly, no statistically significant difference was observed in the amplitude mean values of the Wave III in the intergroup assessment (P > 0.05).
In the intragroup assessment, no statistically significant difference was found in the amplitude mean values of the Wave V in all the three groups on the assessment days (P > 0.05). Similarly, there was no statistically significant difference between the amplitude mean values of the Wave V in intergroup assessment (P > 0.05).
| Discussion|| |
Imatinib is specifically a BCR/ABL tyrosine kinase inhibitor. In patients with CML, imatinib has become a standard treatment protocol in CML treatment by obtaining a major cytogenetic response over 80% with imatinib in CML patients.,, Imatinib is considered as the initial treatment option in both adult and pediatric CML patients. However, its continuous use is required. Side effects of imatinib are quite few. These side effects can be classified as hematological and nonhematological side effects. Among the most common nonhematological side effects, peripheral and periorbital edema, muscle cramps, gastrointestinal intolerance, skin rashes, and rarely heart failure may be observed.
Ototoxicity is not specified among the side effects of imatinib. However, in the literature, we have encountered 9 publications upon using the key words of “imatinib and hearing,” 8 publications upon using the key words of “imatinib and hearing loss,” and 3 publications upon using the key words of “imatinib and ototoxicity” in the PubMed database. When these studies and case reports are reviewed, the correlation between imatinib and ototoxicity was not mentioned in the publications of Sathornsumetee et al., Sabha et al., and Lim and de Souza. The first case report pointing out the correlation between imatinib and hearing loss was reported by Attili et al. in 2008. They considered that after all etiologic possibilities were eliminated in the cases for which they determined sensorineural hearing loss (SNHL) holding sudden-onset, bilateral, severe, and high frequencies during clinical follow-ups, imatinib might have caused this hearing loss. If they took the case in clinical follow-up after interrupting medication, they did not determine any recovery in hearing at the end of 2 months and shared this with the literature. In the literature, Janssen et al. reported a progressive hearing loss in 12 months of treatment due to cerebral edema in a case with CML having a major molecular response to imatinib treatment in their study. Although it is known that cerebral edema can be observed as a side effect of imatinib, Janssen et al. could not conclude that cerebral edema monitored in their cases could be a side effect of imatinib because drug treatment was applied for longer than 1 year, however, they thought that they could not exclude this possibility and they observed that the clinic of the patient began to improve rapidly when they terminated imatinib treatment and started acyclovir and dexamethasone treatment. When cerebrospinal fluid assessment was performed in order to exclude intracranial infection and tumor possibilities in their cases, it was determined that the observed neurologic symptoms were not associated with cerebral edema induced by imatinib but was a result of blast crisis emerging in the central nervous system due to the primary disease. Lin et al. primarily tried to reduce the dose of imatinib mesylate because no new medication was started in cases having hearing loss complaints from bilateral flux 1 month after the imatinib mesylate treatment was started due to nephrogenic fibrosis. However, during the follow-up of the case, oral prednisolone treatment such as sudden hearing loss was started due to the increase in hearing loss in pure-tone audiogram, however, no improvement was observed in hearing. They pointed out that imatinib could have a cumulative neurotoxic effect on auditory nerve since there was fluctuation in hearing of the cases during their follow-ups and a decrease was also observed in their word discrimination scores. Kurosawa et al. showed that imatinib treatment had no effect on hearing loos and other symptoms in children with CML with leukocytosis. Wasif et al. reported that irreversible bilateral SNHL was detected in a patient with gastrointestinal tract tumor, who was treated with imatinib. The final publication we reached about imatinib and hearing loss is a literature review of Gupta et al., regarding the effect of imatinib mesylate on hearing and vestibular functions of the cases with CML, and is the most extensive assessment on this matter. They concluded that tyrosine kinase inhibitors did not cause any disorder in hearing and vestibular functions in cases with CML according to the results obtained by this preclinical study.
As is known, imatinib is a tyrosine kinase inhibitor that is well tolerated and that has quite few and negligible side effects. However, all the tyrosine kinase inhibitors may cause some undesired side effects by affecting both the target and nontarget receptors. Neurological side effects are also relatively few. However, imatinib is a highly new antineoplastic drug and its some side effects that have not been identified or reported in initial periods may occur during their long-term use.,, Attili et al. pointed out that the underlying mechanism of rare side effects such as ototoxicity, cardiotoxicity, and optic neuritis may be the mitochondrial dysfunction caused by imatinib. However, ther was not found any study showing that there may be a correlation between the neurotoxic side effects and mitochondrial dysfunction was found. Various types of tyrosine kinase receptors, including TrkB and TrkC, are expressed in the primary auditory neurons of mammals. Imatinib or other tyrosine kinase inhibitors may cause hearing loss by affecting these receptors. The results of this study conducted to investigate whether or not imatinib has an ototoxic effect are remarkable. Because Wave V latency prolongation in the high-frequency region in the high-dose drug group, and also the presence of significant prolongation in the Wave III latency in the drug groups, but not observed in the control group might be suggest the ototoxicity. The prolongation observed in the Wave V latency indicates that the ototoxic effect may have started at the inferior colliculus level. However, monitorization of this prolongation at a single frequency and in a single group is not sufficient to assert that the drug is ototoxic. Similarly, the prolongation observed in the Wave III latency can be accepted as an indicator for the fact that cochlear nuclei might have been affected due to imatinib. However, we have no definite conclusions that allow to clearly express ototoxicity.
In conclusion, due to the limitations in the study, it was not possible to say whether or not imatinib has an ototoxic effect in the present study planned to investigate the presence of an ototoxic side effect of imatinib. These limitations include that the drug doses used in the assessment of the cardiotoxic effect of imatinib on the rats were taken as a basis, the drug treatment was limited with 21 days although it is used lifelong in the cases with CML, hearing was assessed in rats only by ABR, otoacoustic emission test was not performed to observe the influence in cochlea well, and cochlea was not assessed in terms of histopathology and electron microscope. Although the present study contributes to the literature since it is the first study evaluating ototoxic side effects of drugs in imatinib and drugs in a similar group due to all of these limitations, it is a preliminary study.
| Conclusion|| |
The present study is a preliminary study because it is the first experimental study in the literature investigating the effects of imatinib on hearing. When the results of the present study are carefully evaluated and interpreted, it is considered that imatinib may have an ototoxic effect, but further studies are needed to clarify the molecular background of the effect of the tyrosine kinase inhibitors to the inner ear in order to exactly to determine this matter.
We would like to thank Selim Çam for his contribution to statistical evaluation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]